Bone growth protein offers hope for newborns with rare lung disease

Babies born with alveolar capillary dysplasia and pulmonary venous malformation (ACDMPV) lack oxygenated blood in their systems

However, researchers at Cincinnati Children's Hospital Medical Center have been studying how ACDMPV develops and now propose a possible treatment after using a mouse model

Lung endothelial progenitor cells (EPCs) are critical for neonatal pulmonary angiogenesis and are a subset of general capillary cells (gCAPs)

"Here, we used single-cell RNA-sequencing to identify BMP9/ACVRL1/SMAD1 pathway signatures in lung endothelial progenitor cells.

"Inhibition of the FOXF1 transcription factor reduces BMP9/ACVRL1 signaling and reduces angiogenesis in vitro.

In conclusion, EPCs promote neonatal pulmonary angiogenesis and alveolarization through foxf1-mediated activation of the BMP9/ACVRL1 signaling pathway

"BMP9 treatment effectively restored capillary density, improved alveolarization, increased arterial oxygenation, increased BMP9 receptor expression on the surface of capillary endothelial cells Acvrl1, and improved survival in a mouse model of ACDMPV

Isolation of key molecular signaling pathways

The study describes the research team sifting through a large number of single-cell RNA-seq data collected from more than 7,000 lung cells from mice carrying a gene mutation with ACDMPV (loss of the human gene FOXF1) and another nearly 6,000 normal lung cells to find one of the diseases The devastating results of cell type creation

The work began by isolating 12 potentially interesting cell populations

Using data from 800 of these cells, the team found that 93 genes were down-regulated and 43 genes were up-regulated in the Foxf1 mutant group compared to the normal group

When the FOXF1 protein is absent or contains a deleterious mutation, the expression of Acvrl1 is reduced, which in turn reduces the expression of downstream target genes

To assess the importance of this pathway requires the use of a nanoparticle delivery platform developed in Kalinichenko's lab to silence the ACVRL1 protein -- but only in endothelial cells in mouse lungs

The researchers found that adding the synthetic bone morphogenetic protein BMP9 to cells lacking a functional FOXF1 gene helped rebuild the signaling pathway, stimulated Acvrl1 activity, and instructed the lungs to continue making capillaries

BMP9 is one of about 20 different such proteins found in humans

Two other related proteins - bmp7 and bmp2 - have been approved by the FDA for the treatment of bone growth disorders

If a safe BMP9 agonist or a synthetic BMP9 molecule suitable for human use could be developed, it could be more than a treatment strictly for ACDMPV, Galinichenko noted
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It may also stimulate blood vessel growth, which can be hindered by bronchopulmonary dysplasia (BPD)
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BPD is a complication of preterm birth that occurs in approximately 10,000 to 15,000 babies each year
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While most babies survive, early intervention can stimulate repair of lung damage and help prevent an increased risk of asthma and lung infections later in life
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This treatment may also ultimately benefit infants with congenital diaphragmatic hernia (CDH)
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In these children, the gap in the diaphragm allows other internal organs to squeeze into the space needed by the lungs
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While surgery can repair a hernia, in many cases it is difficult for the lungs to grow back to normal
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